Physiological means of enhancing transdermal delivery of drugs

ABSTRACT

A method of enhancing transdermal delivery of a pharmaceutically active drug from a transdermal delivery system as well as a transdermal delivery system capable of providing a desirable flow interface between the delivery system and the skin surface are disclosed. The method involves pre-treating an area of skin with an anticholinergic agent in an amount sufficient to have a local antisecretory effect on the area treated, such amount being insufficient to cause systemic effects; and applying the transdermal delivery system to the pre-treated area. The delivery system of the present invention is comprised of a carrier means, a pharmaceutically active drug and an anticholinergic agent. With both the method and the delivery system, the anticholinergic agent is preferably a quaternary ammonium salt which is itself transdermally delivered to the area beneath the delivery system in an amount sufficient to suppress perspiration in that area. The suppression of perspiration prevents the formation of an aqueous interface between the skin and delivery system which might prevent drug delivery.

This application is a divisional of Ser. No. 014,317, filed Feb. 13,1987 now U.S. Pat. No. 4,824,676, which is a continuation in part ofapplication Ser. No. 659,919, filed Oct. 11, 1984, now abandoned.

FIELD OF THE INVENTION

The present invention relates to the field of transdermal deliverysystems and to methods of enhancing the transdermal delivery ofpharmaceutically active drugs from such systems. More specifically, theinvention relates to such systems which include an anticholinergic agentin an amount sufficient to have a local antisecretory effect on skin,such an amount being insufficient to cause a systemic effect. Theinvention also relates to pre-treating the skin with anticholinergicagents so as to locally inhibit secretion from the skin and therebyeliminate the formation of an aqueous layer between any delivery systemand the skin so as to enhance penetration of drugs from transdermaldelivery systems.

BACKGROUND OF THE INVENTION

It is well known that many drugs if taken orally, are destroyed on thefirst past through the liver. It is also well known that when many drugsare taken orally, their rate of absorption into the body is notconstant. In view of such difficulties, a number of different drugdelivery systems have been developed. Recently, the use of transdermaldelivery systems have met with increasing interest by researchers in thepharmaceutical drug delivery field.

U.S. Pat. No. 4,291,015 to Keith, et al. discloses the use of apolymeric diffusion matrix for the sustained release of pharmaceuticallyactive drugs. The matrix is covered by a backing layer and applied tothe skin where diffusion of the pharmaceutically active drug occurs andthe drug is transdermally delivered to the patient. Although U.S. Pat.No. 4,291,015 discloses transdermal delivery of nitroglycerin, otherdrugs may be delivered by utilizing the same or a similar matrix, asdisclosed in U.S. Pat. Nos. 4,294,820; 4,292,302; and 4,292,303.

U.S. Pat. No. 4,409,206 discloses the use of a different type oftransdermal delivery system whereby the pharmaceutically active drug isdispersed within an adhesive (see also U.S. Pat. No. 4,390,520). Inaccordance with such systems, the pharmaceutically active drug isdispersed in a pressure-sensitive adhesive which is adhered to the skin.The drug then diffuses from the adhesive through the skin for deliveryto the patient.

Other transdermal systems involve the use of a matrix which is indiffusional contact with a reservoir which contains the pharmaceuticallyactive drug. The drug diffuses to the matrix and then to the skin andeventually to the patient. Still other compositions include an activeingredient in a salve or ointment which is applied to skin. The activeingredient diffuses from the salve to the skin and enters the bodytransdermally.

Each of the systems have various advantages and disadvantages withrespect to the transdermally delivery of pharmaceutically active drugs.Certain systems may be useful in connection with one type ofpharmaceutically active drug and not useful in connection with another.The ability to include one pharmaceutically active drug within a givensystem depends on various factors such as the compatibility of the drugwith the system and the effects of the drugs on the system such as itsability to dissolve in the system. Without experimentation, it is oftenimpossible to accurately predict the usefulness of any particular systemwith any particular pharmaceutically active drug. However, the presentinventor has found that all the systems do have certain similarities andmore importantly a common undesirable feature. More specifically, theyall operate by transporting the pharmaceutically active drug to the skinfor transdermal delivery. In order to accomplish this, the system mustbe placed in intimate contact with the skin. Since normal skin willperspire such will create an aqueous layer between the skin and thesystem. It is this aqueous layer which causes the common disadvantage.

Perspiration may well be increased beneath a transdermal delivery systemand any perspiration beneath a delivery system causes an outflow ofwater and other water soluble body salts from the skin. This increasedoutflow increases the size of the aqueous layer and thus hinders thedesired inflow of the pharmaceutically active drug through the skin.When the system remains in place for a substantial period of time (24hours is common), the outflow of perspiration can build up a substantialaqueous layer between the delivery system and the skin. This impedimentis especially great if the pharmaceutically active drug is insolublewith respect to the aqueous layer or if the drug is in any wayincompatible with the aqueous layer or coagulates upon contact with it.The present invention is directed to elimination of the undesirableoutflow of perspiration from the skin and the undesirable accumulationof that perspiration (aqueous layer formation) between the skin and thedrug delivery system.

SUMMARY OF THE INVENTION

In its simplest form, the present invention involves the localapplication of an anticholinergic, preferably an anhidrotic agent, tothe skin to prevent perspiration and thus indirectly enhance transdermaldelivery of a pharmaceutically active, preferably non-anticholinergic,drug. Local application may be carried out by pre-treating an area ofskin with an anticholinergic agent in an amount sufficient to have alocal antisecretory effect on the area treated, such amount beinginsufficient to cause a systemic effect, and then applying a transdermaldelivery system to the pre-treated area. Alternatively, the inventioncan be carried out by including the anticholinergic agent with thetransdermal delivery system in such a manner that the anticholinergicagent can be delivered through the skin to prevent perspiration. Theanticholinergic agent may be incorporated in a diffusion matrix,dispersed in a reservoir connected to such a matrix, included in aseparate reservoir, dispersed in an ointment or connected in any othermanner making it possible for the delivery of the anticholinergic agentthrough the skin to which the transdermal delivery system will beapplied.

It is a primary object of the present invention to provide aphysiological means of enhancing transdermal delivery of drugs.

Another object of the present invention is to deliver, to an area ofskin, an anticholinergic agent in an amount sufficient to have a localantisecretory effect on the area of skin, such amount being insufficientto cause a systemic effect.

Yet another object of the invention is to provide a method of enhancingthe transdermal delivery of a pharmaceutically active drug from atransdermal delivery system by

Pharmaceutically active drugs for use in the present invention includetransdermally deliverable physiologically or pharmacologically activesubstances for producing a localized or systemic effect in mammals,especially humans. The active drugs that can be used in the presentinvention are well known. See for example, U.S. Pat. No. 3,921,636wherein one may find the following list of transdermally deliverabledrugs: drugs acting on the central nervous system, such as hypnotics andsedatives such as pentobarbital sodium, phenobarbital, secobarbital,thiopental, etc; heterocyclic hypnotics such as dioxopiperidines, andglutarimides; hypnotics and sedatives such as amides and ureasexemplified by diethylisovaleramide and α-bromoisovaleryl urea and thelike; hypnotics and sedative alcohols such as carbomal,naphthoxyethanol, methylparaphenol and the like; and hypnotics andsedative urethans, disulfanes and the like; psychic energizers such asisocarboxacid, nialamide, phenelzine, imipramine, tranylcypromine,pargylene and the like; tranquilizers such as chloropromazine,promazine, fluphenazine, reserpine, deserpidine, meprobamate,benzodiazepines such as chlordiazepoxide and the like; anticonvulsantssuch as primidone, diphenylhydantoin, ethotoin, pheneturide,ethosuximide and the like; muscle relaxants and antiparkinson agentssuch as mephenesin, methocarbomal, trihexylphenidyl, biperiden,levo-dopa, also known L-dopa and 1-β-3-4-dihydroxyphenylalanine, and thelike; analgesics such as morphine, codeine, meperidine, nalorphine andthe like; anti-pyretics and anti-inflammatory agents such as aspirin,salicylamide, sodium salicylamide and the like; local anesthetics suchas procaine, lidocaine, naepaine, piperocaine, tetracaine, dibucaine andthe like; antispasmodics and antiulcer agents such as papaverine,prostaglandins such as PGE₁, PGE₂, PGF_(1a), PGF_(2a), PGA and the like;antimicrobials such as penicillin, tetracycline, oxytetracycline,chlorotetracycline, chloramphenicol, sulfonamides and the like;anti-malarials such as 4-aminoquinolines, 8-aminoquinolines andpyrimethamine; hormonal agents such as prednisolone, cortisone, cortisoland triamcinolone; androgenic steroids, for example methyltestosterone,fluoximesterone and the like; estrogenic steroids, for example,17β-estradiol and ethinyl estradiol; progestational steroids, forexample 17α-hydroxyprogesterone acetate, 19-nor-progesterone,norethindrone and the like; sympathomimetic drugs such as epinephrine,amphetamine, ephedrine, norepinephrine and the like; cardiovasculardrugs, for example, procainamide, amyl nitrate, nitroglycerin,dipyridamole, sodium nitrate, mannitol nitrate and the like; diuretics,for example, chlorothiazide, flumethiazide and the like; antiparasticagents such as bephenium hydroxynaphthoate and dichlorophen, dapsone andthe like; neoplastic agents such as mechlorethamine, uracil mustard,5-fluorouracil, 6-thioguanine, procarbazine and the like; hypoglycemicdrugs such as insulins, protamine zinc insulin suspension and other artknown extended insulin suspensions, sulfonylureas such as tolbutamide,acetohexamide, tolazamide, and chlorpropamide, the biguanides and thelike; nutritional agents such as vitamins, essential amino acids,essential fats and the like; and other physiologically orpharmacologically, active agents. Also the drugs can be present as thepharmacologically acceptable derivatives, such as ethers, esters,amides, acetals, etc. that lend themselves to passage into thecirculatory system.

As indicated above, the systems have various advantages, disadvantages,and degrees of usefulness in connection with pre-treating an area ofskin with an anticholinergic agent and applying a transdermal deliverysystem to the pre-treated area.

Another object of the invention is to provide a transdermal deliverysystem capable of providing a desirable flow interface between thedelivery system and skin surface, comprising a carrier means, apharmaceutically active drug and an anticholinergic agent present in anamount sufficient to have a local antisecretory effect on the skin belowthe system, such amount being insufficient to cause a systemic effect.

Yet another object of the invention is to provide such systems and meanswhereby the anticholinergic agents are quaternary ammonium salts of suchagents.

These and other objects of the invention will become apparent to thoseskilled in the art upon reading this disclosure.

DETAILED DESCRIPTION OF THE INVENTION

There are a number of known chemical compounds which are known as"penetration enhancers". Such compounds interact in some manner with apharmaceutically active drug and enhance the penetration of that drugthrough the skin. Perhaps the most famous of such penetration enhancersis "DMSO (dimethyl sulfoxide)". However, DMSO has not received FDAapproval for use on humans. Another well known penetration enhancer isAZONE, see U.S. Pat. Nos. 3,989,816, 4,311,481 and 4,316,893 as well asthe corresponding foreign patents.

Such known penetration enhancers have a physical and/or chemical meansof enhancing the penetration of the pharmaceutically active drug. Suchcompounds may themselves be easily transported through the skin and thusenhance the skin permeability, allowing transport of thepharmaceutically active drugs at significantly higher flux. Theenhancers may also have the effect of neutralizing molecular charges onthe pharmaceutically active drugs, thus making them more susceptible topenetration of the skin.

Although such penetration enhancers are useful and might even be used incombination with the present invention, they do not cause the samephysiological effect on the skin as does the present invention.

After making a thorough study of the transdermal delivery systems, thepresent inventor found that the transdermal delivery of pharmaceuticallyactive drugs through the skin could be hindered by the outflow ofperspiration from the skin and subsequent formation of an aqueous layerover the skin. The present inventor noted that transdermal deliverysystems were normally worn for a long period of time, generally abouttwenty-four hours (24). When delivery systems are worn for such extendedperiods of time, substantial perspiration from the skin is very likelyto build up between the outer layer of the skin and the contact layer ofthe transdermal delivery system. The aqueous layer of perspiration thusformed between the delivery system and the skin interrupts the desiredinterface between the skin and the delivery system having an undesirableeffect on the delivery of drugs from the system.

The present inventor noted that the above referred to problem could attimes, be at least partially remedied by including additionalpharmaceutically active drug into the delivery system. Such a solutionis, of course, only possible where additional drug may be incorporatedinto the system without having undesirable effects. Such effects maytake place where the pharmaceutically active drug acts as a solvent withrespect to the system causing dissolution of the system. Further, evenin situations where additional drug can be incorporated into thedelivery system the problem is not completely solved in that individualsvary with respect to the amount they perspire and even a givenindividual may generate greatly different amounts of perspirationdepending on the temperature, humidity and activity of the individual.

Due to individual differences in the amount of perspiration generated aswell as the amount of perspiration a particular individual might begenerating at any particular time, the present inventor found that therate of drug delivery from a transdermal drug delivery system couldvary. Such variance in the amount of drug delivered is, of course,undesirable in that he physician would prefer to prescribe a deliverysystem with which an accurate determination could be made with respectto the rate of delivery of the pharmaceutically active drug. Therealization of the problems caused by perspiration when utilizing thetransdermal delivery systems precipitated the discovery of the presentinvention by the present inventor.

After determining that perspiration from the skin causes problems withtransdermal delivery systems, the present inventor determined thatpreventing that perspiration would solve the problems related thereto.According, an examination of various compounds utilized for preventingperspiration was made. Commercially available antiperspirants normallysold in the form of roll-ons and sprays are effective in preventingperspiration. Such compositions are normally aluminum based and preventperspiration by a physical blocking means, i.e. the compounds actuallyclog the canals through which the perspiration passes. Since suchcompounds actually operate by clogging the passage ways out of the skin,the use of such compounds might not be desirable with respect toincreasing the inflow of a pharmaceutically active drug through theskin. Although use of such compounds might avoid the formation of anaqueous layer between the skin and the transdermal delivery device, suchcompounds might themselves create barriers for the inflow ofpharmaceutically active drugs through the skin.

The present inventor has done substantial work with anticholinergiccompounds as shown in U.K. Patent No. 2,010,270 which discloses softanticholinergic agents exhibiting antisecretory activity. Accordingly,the present inventor carried out experiments in order to determine ifthe use of such anticholinergic compounds would inhibit the inflow ofpharmaceutically active drugs from a transdermal delivery device andfound that the inflow of drugs was not inhibited. Knowing that suchanticholinergic drugs prevented the outflow of perspiration and thus theformation of any aqueous layer, it was deduced that the effects ofanticholingeric agents would increase the inflow of pharmaceuticallyactive drugs through the skin.

Anticholinergic drugs affect the nervous system. The systemic effect onthe nervous system is undesirable in connection with the presentinvention. Accordingly, the topical application of a small amount ofanticholinergic agents to the skin is all that is necessary anddesirable in order to obtain the results of the invention.

The normal working physiology of a human being provides a neurohumoraltransmitter substance which provokes a stimulant action. For example,such a substance can evoke a stimulant action with respect to secretionglands within the skin and cause perspiration. However, within thenormal physiology with a human, there is no comparable substance whichprovides an inhibitory action. There are, however, synthetic andplant-produced compounds that provide such inhibitory action. Suchcompounds act by blocking synaptic transmission in either thesympathetic or parasympathetic innervations. The present inventor notedthat the blocking action of these inhibitors is usually quite specificto its locus. The use of such agents can cause blocking at theganglionic nerve terminations (synapses) in either the sympathetic orparasympathetic ganglia, at the post ganglionic nerve terminations ofeither system (nerve-muscle junction blocking agent).

A chart is set forth below showing the various sites of blocking actionof anticholinergic agents.

    __________________________________________________________________________    AUTONOMIC BLOCKING AGENTS                NEUROHUMORAL    SITE OF BLOCKING                TRANSMITTER                           TYPE OF BLOCKING                                       EXAMPLE OF    ACTION      SUBSTANCE  ACTION      DRUG    __________________________________________________________________________    Sympathetic Acetylcholine                           Anticholinergic                                       Hexamethonium    Ganglion    Postganglionic    Synapse     Norepinephrine                           Antiadrenergic                                       Dibenamine                (and epinephrine)    Parasympathetic    Ganglion    Acetylcholine                           Anticholinergic                                       Hexamethonium    Postganglionic    Synapse     Acetylcholine                           Anticholinergic                                       Atropine    Voluntary*  Acetylcoline                           Anticholinergic                                       Curare    Neuromuscular    Junction    __________________________________________________________________________     *Included as a matter of convenience and because of certain similarities     with the ganglionic blocking agents. These drugs are not autonomic     blocking agents.

A number of different therapeutic actions can be obtained by the use ofanticholinergic agents. The effect of such agents include the following:

(1. Mydriatic effect (dilation of pupil of the eye) and cycloplegia (aparalysis of the ciliary structure of the eye, resulting in a paralysisof accommodation for near vision).

2. Antispasmodic effect (lowered tone and motility of thegastrointestinal tract and the genitourinary tract).

3. Antisecretory effect (reduced salivation (antisialogogue), reducedperspiration (anhidrotic) and reduced acid and gastric secretion).

As indicated above the anticholinergic agents have a substantial numberof different effects on the human body. Accordingly, it is undesirableunless absolutely necessary to prescribe such agents in an amount suchthat they have a systemic effect. Therefore, it would be undesirable toprescribe such anticholinergic agents for oral usage simply to preventperspiration which would then indirectly facilitate transdermal deliveryof a drug from a transdermal delivery system. The mechanism of action ofsuch drugs is obscure, but such drugs do affect a central mechanism.However, in order to affect a central mechanism and have a systemiceffect the compounds must pass the blood-brain barrier. Upon research,it was found that tertiary amines of such anticholinergic compounds canpass this blood-brain barrier but that quaternary ammonium compoundscould not.

Tertiary amines of certain anticholinergic compounds have been shown toincrease the brain acetylcholine levels in rats up to 40%. This increasecoincides roughly with the onset of tremors similar to those observed inparkinsonism. The mechanism of acetylcholine increase in rats isuncertain but it has been shown not to be due to acetylcholinesteraseinhibition or to activation to acetylase. However, the tremors arestopped effectively by administration of the tertiary amine typeanticholinergic but not by the quaternary ammonium compounds.

Although any of the anticholinergic compounds can prevent secretion andthus aide in the transdermal delivery of a drug from a transdermaldelivery system, due to the undesirable side effects of some of thesecompounds, the present inventor determined that it would be mostdesirable to utilize quaternary ammonium salts of known anticholinergiccompounds, and has further determined that the topical application ofsuch compounds in small amounts would be most desirable in terms ofobtaining the desired effects of the present invention and avoidingundesirable side effects.

The following are specific examples of quaternary ammonium salts ofanticholinergic compounds preferably used in connection with the presentinvention. ##STR1##

In order to describe some aspects of how the present invention works,the mechanism of a specific compound will be discussed. It is generallyagreed that the activity of atropine-related anticholinergics is acompetitive one with acetylcholine. Accordingly, the cholinomimeticagent (i.e. acetylcholine) possesses both affinity and intrinsicactivity and can be bound to the receptor site and elicit thecharacteristic mimetic response. The anticholinergic agent, on the otherhand, has the necessary affinity to bind firmly to the receptor but isunable to bring about an effective response, i.e., it has no intrinsicactivity. The blocking agent, in sufficient concentration effectivelycompetes for the receptor sites and prevents acetylcholine from bindingthereon, thus preventing nerve activity.

With the present invention, the anticholingeric molecules have a primarypoint of attachment to cholinergic sites through the so called cationichead, i.e., the positively charged nitrogen present on the quaternaryammonium salts preferably used in connection with the present invention.Accordingly, the quaternary ammonium salts of anticholinergic agentspreferred for use in the present invention actually penetrate the skinand attach themselves on receptor sites. This prevents other agentswhich cause intrinsic activity from attaching to that site. Whentopically applied to the skin the anticholinergic agent physiologicallyinterrupts the normal course of events and prevents perspiration. Unlikeantiperspirants which are sold commercially, the anticholinergic agentsof the present invention do not cause a physical blocking of anychannels from which perspiration flows. The compounds of the presentinvention simply prevent secretion before it starts.

In order to determine if the anticholinergic agents of the presentinvention had any negative effect on the delivery of pharmaceuticallyactive drugs from a transdermal delivery system, the inventor tested theinvention on hairless mice. Knowing that hairless mice do not perspire,an anticholinergic agent was topically applied to an area of skin onhairless mice and a transdermal delivery system was then applied overthe area to which the anticholinergic agent was applied. An identicaltransdermal delivery device was applied to a different mouse to which noanticholinergic agent had been applied. The inventor found that bothmice received the same amount of pharmaceutically active drug from thetransdermal delivery system. Accordingly, it was deduced that the use ofthe anticholinergic agent had no effect on the transdermal delivery orthe drug in an in vivo environment where no perspiration occurs. Thepresent inventor then further deduced that the topical application ofanticholinergic agents to human skin (where perspiration does occur)would facilitate the delivery of drugs from transdermal delivery systemsin that such agents clearly do effectively prevent perspiration.

As indicated above, any type of anticholinergic agent can be utilized inconnection with the present invention. However, the present inventorbelieves that quaternary ammonium compounds as indicated above and thosedisclosed within U.K. Patent No. 2,010,270 are preferably used inconnection with the present invention. Compounds disclosed therein areof the general formula I or II below: ##STR2## wherein represents atertiary amine, ##STR3## represents an unsaturated amine and R₂ R₃ andR₄ (which may be the same or different provided that at least two of thegroups represented by R₂, R₃ and R₄ must be other than a hydrogen atom,and provided that R₂, R₃ and R₄ together must contain at least 5 carbonatoms) each represents a hydrogen atom, a straight or branched-chainalkyl or alkoxy group having from 1 to 8 carbon atoms, a cycloalkyl orcycloalkenyl group having up to 8 carbon atoms, an alkoxyalkyl,acyloxyalkyl, haloalkyl or carboxyalkyl group each having up to 8 carbonatoms, an alkenylphenyl group having up to 8 carbon atoms in the alkenylmoiety, an aryl group (unsubstituted or substituted by a halogen atom,an alkoxy group having from 1 to 4 carbon atoms, an acyloxy group, anitro group, a carboxyl group or a carboethoxy group), a CH₂ OH group, a--CHOCOR₁ group (wherein R₁ is as defined below or a -- CH₂ ONO₂ group),an --OH group, a halogen atom or a --OCOR₁ group (wherein R₁ is asdefined below) or a --ONO₂ group; or R₂ is as hereinbefore defined andR₃, R₄ and the carbon atom to which they are attached form a cyclo-alkylgroup having up to 8 carbon atoms; or the groups represented by R₂ R₃and R₄ and the carbon atom to which they are attached form a fusedpolycarbocyclic ring or a polyheterocyclic ring; and R₁ represents anygroup which is capable of being represented by R₂ R₃ or R₄ ashereinbefore defined; --X-- represents --O-- or --S--; and Y representsa halogen atom or any other organic or inorganic anion.

In the above formulae, reference to "aryl" denotes a phenyl or naphthalgroup; reference to "halo" and "halogen" in each occurrence, denotes anysuitable member of the halogen series, for example, chlorine, bromine oriodine; and reference to "acyl" in the expression "acyloxyalkyl" and"acyloxy" denotes any convenient carboacyl group, such as a formylgroup, an acetyl group, a propionyl group, a benzoyl group, etc. It isfurther noted that the term "substituted" when applied to the aryl grouprefers to the fact that the aryl function may be substituted with anyone or more of those substituents specifically defined herein. Withregard to substituent "Y", when this substituent is other than halogen,methanesulfonate, fluorosulphate or tosylate are preferred.

Finally, with respect to the expression "unsaturated amine", thisexpression is intended to include N-heterocyclic unsaturated systemshaving 3-10 members in the ring, and substituted derivative thereofwhere the unsaturation corresponds to the maximum number ofnon-cumulative double bonds, provided that the nitrogen atom contains nohydrogen atom as a substituent.

The anticholinergic agents which are quaternary ammonium salts as shownabove and disclosed in U.K. Patent No. 2,010,270 are believed to be moreuseful in connection with the present invention in that they are "soft"in nature, i.e., these agents exhibit substantial anticholinergicantisecretory activity, while having low toxicity following therapeuticapplication. They do not pass the "brain barrier." Other anticholinergicagents exhibit substantial anticholinergic antisecretory activity, butin addition these compounds give rise to a number of toxic side effectssuch as dizziness, blurred vision and dry mouth.

In order to obtain the effects of the present invention small amounts ofthe anticholinergic agents are utilized. For example, a usefulcomposition can be prepared using anisotropine methylbromide (Valpin) asthe anticholinergic agent (see Merck Index Tenth Edition, Entry Number693). This agent is very soluble in alcohols. Accordingly, 20 milligramscan be dissolved in 25 milliliters of ethanol and 200 microliters of thesolution can be applied to about five or six square centimeters of skinsurface. This amount will prevent perspiration from that area for aperiod sufficient for the purposes of the present invention, i.e. abouttwenty-four (24) hours or more.

In order to make use of the present invention the anticholinergic agentscan be dissolved in any suitable dermatologically acceptable solvent andapplied by any known means to the surface area of skin to which atransdermal delivery device is to be applied. Alternatively, the agentsmay be included in any transdermal system. The anticholinergic agents ofthe invention are themselves capable of migrating transdermally.Accordingly, they can be merely placed on the skin, rubbed into theskin, sprayed on the skin or placed in contact with the skin as part ofthe transdermal delivery system. In order to obtain a cleansing effectwhich is an additional benefit when utilizing a transdermal deliverydevice, the anticholinergic agent can be placed onto an applicator suchas a cotton swab or cloth which has the agent thereon dissolved inalcohol. The applicator having the agent dissolved thereon is thenrubbed on the area of skin to which the device is to be applied. Thealcohol has a cleansing antiseptic effect on the area and theanticholingeric compound is allowed to permeate the skin. Thetransdermal delivery device is then applied over the area which has beenpre-treated. An agent known to enhance skin penetration might also beincluded on the applicator.

In addition to pre-treating an area of skin with an anticholinergicagent, it is possible to utilize the present invention by incorporatingthe anticholinergic agent into the transdermal delivery system. Thepenetration enhancers present in such a system might also enhancepenetration of the anticholinergic agent. The agents of the inventioncan be incorporated into a matrix system, included into a reservoir witha pharmaceutically active drug, dispersed in an adhesive layer orointment or otherwise included in connection with the system in somemanner so that the agent may be delivered through the surface of theskin.

As indicated above, a large number of different types ofpharmaceutically active drugs are now being considered for use intransdermal delivery systems. Further, as indicated above, a largenumber of different types of systems are utilized for delivering thesedrugs. Since the present invention can conceivably be used in connectionwith all types of transdermal delivery systems, the present inventorconceived of a preferred embodiment of his invention whereby theinvention could be utilized in connection such systems withoutsubstantial modification.

More specifically, anticholinergic agents of the invention could beabsorbed on an applicator such as a piece of cotton cloth or othersuitable soft pliable material, preferably in an alcohol type solvent.The solvent must be dermatologically acceptable and preferably haveantiseptic properties. The applicator having the anticholinergic agentabsorbed thereon is then incorporated into a separate packet orreservoir which is connected to the transdermal delivery system. Thispacket or reservoir can be opened prior to the application of thetransdermal delivery system. Upon opening, the applicator is removed andthe area of skin to which the system is to be applied is pre-treated byrubbing the area of skin with the applicator, thus cleansing the skinand allowing for transdermal delivery of the anticholinergiccomposition. After pre-treatment, the transdermal delivery device isapplied to the pre-treated area. Delivery of the pharmaceutically activedrug from the transdermal delivery system should be facilitated by thepresent invention in that perspiration from the pre-treated area of skinwill be interrupted thus preventing the outflow of water from that areaof skin and preventing the build up of any aqueous layer between thesurface of the skin and the transdermal delivery system.

The present invention has been disclosed and described herein in what isbelieved to be its more preferred embodiments. However, upon readingthis disclosure those skilled in the art will recognize modificationsand variations thereof which are intended to be within the scope of thepresent invention.

I claim:
 1. In an improved method of transdermally delivering apharmaceutically active non-anticholinergic drug from a transdermaldelivery system applied to an area of skin to provide transdermaldelivery of said active drug through said area of skin, the improvementcomprising:pre-treating said area of skin with an anhidrotic agent in anamount sufficient to have a local antiperspirant effect on the areatreated but insufficient o cause a significant systemic effect, wherebythe transdermal delivery of said pharmaceutically active drug isenhanced and wherein said anhidrotic agent is an anticholinergicquaternary ammonium salt compound.
 2. The method of claim 1 wherein theanhidrotic agent is an antisecretory anticholinergic agent.
 3. Themethod of claim 2 wherein the anhidrotic agent is a quaternary ammoniumsalt.
 4. The method of claim 1 wherein said pre-treating comprisesapplying the anhidrotic agent to an applicator and then rubbing saidarea of skin with said applicator in order to apply said anhidroticagent to said area of skin.
 5. The method of claim 1 wherein saidpre-treating comprises spraying said anhidrotic agent onto said area ofskin.
 6. The method of claim 2 wherein the anticholingericantiperspirant agent is selected from benzilonium bromide,benzomethamine chloride, benzopyrrolate, cyclopyrronium bromide,dihexyverine chloride, heteronium bromide, hexopyrronium bromide,methanetheline bromide, parapenzolate bromide, poldine mesylate,glycopyrrolate, mepenzolate methylbromide, oxyphenonium bromide,penthienate bromide, propantheline bromide, pipenzolate methylbromide,propantheline bromide, diphemanil methylsulfate, hexocycliummethylsulfate, thihexinol methylbromide, tricyclamol, anisotropinemethylbromide, homatropine methylbromide, clindinium bromide,methscopolamine bromide, tridihexethyl chloride, valethamate bromide,ambutonium bromide, dibutoline sulfate, isopropamide iodine, andcompounds of the formulae ##STR4## wherein ##STR5## represents atertiary amine, ##STR6## represents an unsaturated amine and R₂, R₃ andR₄ (which may be the same or difference provided that at least two ofthe groups represented by R₂, R₃ and R₄ must be other than a hydrogenatom, and provided that R₂ R₃ and R₄ together must contain at least 5carbon atoms) each represents a hydrogen atom, a straight orbranched-chain alkyl or alkoxy group having from 1 to 8 carbon atoms, acycloakyl or cycloalkenyl group having from 1 to 8 carbon atoms, acycloalkyl or cycloalkenyl group having up to 8 carbon atoms, analkoxyalkyl, acyloxyalkyl, haloalkyl or carboxyalkyl group each havingup to 8 carbon atoms, an alkenylphenyl group having up to 8 carbon atomsin the alkenyl moiety, an aryl group (unsubstituted or substituted by ahalogen atom, an alkoxy group having from 1 to 4 carbon atoms, anacyloxy group, nitro group, a carboxyl group or a carboethoxy group), a--CH₂ OH group, a --CHOCOR₁ group (wherein R₁ is as defined below or a--CH₂ ONO₂ group), an --OH group, a halogen atom or a --OCOR₁ group(wherein R₁ is as defined below) or a --ONO₂ group; or R is ashereinbefore defined and R₃ R₄ and the carbon atom to which they areattached form a cyclo-alkyl group having up to 8 carbon atoms; or thegroups represented by R₂, R₃ and R.sub. 4 and the carbon atom to whichthey are attached form a fused polycarbocyclic ring or a polyheterocylicring; and R₁ represents any group which is capable of being representedby R₂ R₃ and R₄ as hereinbefore defined; --X-- represents --O-- or--S--; and Y represents a halogen atom or any other organic or inorganicanion.